A Marfan syndrome gene expression phenotype in cultured skin fibroblasts. Homo sapiens

Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts Overall design: Using GF211 spotted cDNA arrays, we compared expression levels of 4132 genes in cultured skin fibroblasts from 17 Marfan subjects and 19 unaffected controls of similar age an sex distribution. On average, each RNA sample was hybridized 2.5 times. Ten selected genes were validated by quantitative real-time PCR in these subjects plus an additional 16 Marfan subjects and 16 controls.